Mucoadhesive Ocular Delivery System for the Treatment of Glaucoma - Patent application

Abstract

The present invention relates to an ocular delivery system useful for the treatment of glaucoma. In particular, the present invention provides a mucoadhesive ocular insert comprising a matrix of a preactivated thiomer of hyaluronic acid and one or more anti-glaucoma drugs.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to the field of ophthalmic formulations and to an ocular delivery system useful for the treatment of glaucoma. In particular, the present invention provides a mucoadhesive ocular insert comprising a matrix of a preactivated thiomer of hyaluronic acid and one or more anti-glaucoma drugs. [Background technology]

[0002] 2. Background of the Invention Glaucoma is a group of eye conditions that can damage the optic nerve and cause vision loss. This damage is often caused by abnormally high pressure within the eye. The most common type is open-angle glaucoma, which develops slowly over time, first causing peripheral vision loss, followed by central vision loss, which can lead to blindness if left untreated. Vision loss due to glaucoma, once it occurs, is permanent. Early treatment can slow and stop disease progression. Treatment of glaucoma can be achieved with medication, laser treatment, or surgery.

[0003] Glaucoma medications aim to preserve visual function by lowering intraocular pressure (IOP) below levels that could further damage the nerves. Different classes of IOP-lowering agents are available, including prostaglandin analogues, cholinergic agonists, beta-blockers, alpha-adrenergic agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors and NO donors. Anti-glaucoma medications are usually administered in the form of eye drops and must be taken for the rest of the patient's life.

[0004] One of the major problems with glaucoma medications is therefore patient compliance with the required daily eye drops. Furthermore, the presence of preservatives in the composition can be irritating and lead to dry eyes.

[0005] Another problem with local ocular administration is obtaining and maintaining sufficient amounts of active substance at the site of action for an extended period of time, and delivering accurate doses of active substance. Aqueous eye drops exhibit the disadvantage of being rapidly cleared after administration, resulting in poor bioavailability. In addition, some antiglaucoma drugs are hydrophobic molecules that are poorly soluble in water.

[0006] Various alternatives to eye drops are available to optimize ophthalmic medications, for example using emulsions, in situ gelling polymers, microspheres, nanoparticles, liposomes or ocular inserts.

[0007] Ocular inserts are solid or semi-solid ocular delivery devices that are placed in the conjunctival sac of the eye. Ocular inserts are an interesting alternative to eye drops because they ensure a longer residence time before the cornea and reduce systemic absorption. For example, US Patent Publication No. 2015 / 157563 discloses an ocular insert that includes a polymer matrix, an antimicrobial agent dispersed therein, and optionally other active substances for controlled release of the active substance. The polymer matrix includes a thiolated hyaluronic acid portion (such as a thiolated carboxymethyl hyaluronic acid (CMHA-S) portion) that is crosslinked to a second portion, which is preferably a poly(ethylene glycol) diacrylate portion (PEGDA). Additional components, such as methylcellulose (MC), are added to provide mucoadhesion.

[0008] Nevertheless, ocular inserts are poorly accepted by patients because in most cases they lead to a sensation of a foreign body in the eye. Moreover, if the insert moves around the eye, it may also interfere with vision and cause irritation, which may further lead to its expulsion from the conjunctival sac and limit the residence time. Another disadvantage of currently available inserts is that their dissolution curve may be too short to allow for drug release over several days.

[0009] Therefore, efforts are being made to provide mucoadhesive ocular inserts that are well tolerated by patients, have release rates of several days, and are still simple to manufacture.

[0010] When an ocular delivery system is placed on the surface of the eye, it first comes into contact with the tear film, which is formed of three layers: a lipid layer, an aqueous layer, and a mucin layer. The mucin present beneath the tear film can therefore be targeted to attach the ocular delivery system to the ocular surface. Several polymers, such as thiomers, have already been tested for their mucoadhesive properties.

[0011] Thiomers, also called "thiolated polymers", are polymers with side chains carrying free thiol moieties (Bernkop-Schnurch A. et al., Pharm. Res., 1999, 16, 876-881; US ​​Patent No. 7,354,600; Bonengel S. and Bernkop-Schnurch A., J. Controlled Release, 2014, 120-129). The polymer backbone of the thiomers usually consists of biodegradable polymers, such as, for example, chitosan, hyaluronic acid, gelatin, polyacrylates, cellulose derivatives, cyclodextrins or silicones. The thiolation of such polymer backbones can be achieved, for example, by coupling cysteine ​​moieties. Thiomers can form covalent bonds, i.e. disulfide bonds, with cysteine-rich subdomains of mucins that coat the mucosa. Such covalent bonds are strong and therefore make it possible to ensure efficient mucoadhesion of dosage forms containing the thiomers over a long period of time.

[0012] Hornof et al. tested mucoadhesive ocular inserts based on thiolated poly(acrylic acid) for the controlled release of eye drops (Hornof et al., J. Controlled Release, 2003, 419-428). Dry ocular inserts are placed in the conjunctival sac of the eye and hydrate in situ to form a hydrogel that exhibits good mucoadhesion. The hydrogel form, contrary to previous ocular inserts, does not cause a foreign body sensation and allows the insert to remain in place due to mucoadhesion. Nevertheless, such thiomeric ocular inserts must remain stored at a non-physiological pH (pH 5 for Hornof et al.'s thiomeric ocular insert) to avoid oxidation of the thiol groups of the thiomers and to maintain them in the reduced form. This is essential to maintain a sufficient amount of free thiol groups available for interaction with mucin. Thus, the main drawback of thiomeric ocular inserts is that they induce irritation and pain due to their non-physiological pH. Moreover, such a pH may not be suitable for carrying some types of active substances, which are not stable under such conditions. Finally, Hornof et al. did not demonstrate drug release from the test inserts for more than 8 hours.

[0013] Therefore, there is a need for new solid or semi-solid ocular delivery systems (including ocular inserts and ocular films) that have effective mucoadhesive properties, are well tolerated by patients, and are suitable for delivery of anti-glaucoma drugs at release rates over several days, preferably greater than 2 days, and more preferably greater than 3 days.

[0014] To that end, the applicant provides herein a mucoadhesive solid or semi-solid ocular delivery system based on a matrix of a pre-activated thiomer of hyaluronic acid for the delivery of anti-glaucoma drugs.

[0015] Preactivated, or S-protected, thiomers are thiomers in which the thiol moiety of the side chain is conjugated with a vitamin B derivative, such as mercaptonicotinic acid, mercapto(iso)nicotinamide, or mercaptopyridoxine, via a disulfide bond (US Patent Publication No. 2012 / 0225024). Mucoadhesive properties of such preactivated thiomers have been reported, for example, for poly(acrylic acid)-cysteine-2-mercaptonicotinic acid (Iqbal J. et al., Biomaterials, 2012, 33, 1528-1535) and for vaginal delivery for hyaluronic acid-L-cysteine-6-mercaptonicotinamide (Nowak J., Int. J. Pharmaceutics, 2015, 478, 383-389).

[0016] In WO2021 / 156435, the Applicant provided for the first time a mucoadhesive solid or semi-solid ocular delivery system comprising a matrix composed of at least one pre-activated thiomer. Nevertheless, to the Applicant's knowledge, the use of pre-activated thiomers of hyaluronic acid has not been reported before for the manufacture of ocular delivery systems such as ocular inserts or ocular films for the delivery of anti-glaucoma drugs.

[0017] The use of hyaluronic acid as the backbone of the pre-activated thiomers used in the ocular delivery system of the present invention is advantageous in terms of gelling properties, ocular tolerance, hydration and lubrication.

[0018] The presence of preactivated thiol groups in the thiomers of hyaluronic acid used in the ocular delivery system of the present invention enhances the stability, mucoadhesion, and tolerance of the thiomers, thus providing the ocular delivery system with expected properties. The delivery system of the present invention in particular exhibits the advantage of extending the residence time of the delivery system at the application site without causing irritation. Patient adherence to treatment is improved when using the delivery system of the present invention compared to the use of eye drops, because it avoids repeated eye drops, thereby improving patient compliance. Furthermore, the therapeutic performance of the antiglaucoma drugs delivered is improved due to their increased bioavailability. In particular, the ocular delivery system of the present invention allows the residence time of the drug to be increased, thus facilitating the diffusion of the drug to the eye. In addition, the thiomers used in the ocular delivery system of the present invention reversibly open the tight junctions of the epithelium, thus enhancing the penetration of the drug. It also allows for sustained release over time and allows for more precise dose delivery compared to the delivery that can be achieved when using eye drops.

[0019] To be suitable for ocular use, the solid or semi-solid delivery systems of the present invention must address several specifications, such as having a shape and size compatible with ocular placement and allowing for proper hydration by controlled swelling. It is also essential that the ocular delivery systems of the present invention are compatible with and resistant to the shear motion induced by the natural movement of the eyeball combined with the permanent blinking of the eyelids. Summary of the Invention

[0020] The present invention therefore provides: - 1 or more antiglaucoma medications; and at least one preactivated thiomer of hyaluronic acid selected from polymeric compounds having a hyaluronic acid backbone with covalently bound side chains comprising groups selected from 2-nicotinic acid disulfide groups, 6-nicotinic acid disulfide groups, 2-nicotinamide disulfide groups, 2-isonicotinamide disulfide groups, 6-nicotinamide disulfide groups, 6-isonicotinamide disulfide groups, and 6-pyridoxine disulfide groups; wherein the pre-activated thiomer of hyaluronic acid has a molecular weight in the range of 100 kDa to 1200 kDa.

[0021] In one embodiment, the ocular delivery system is an ocular insert or an ocular film.

[0022] In one embodiment, the side chain of the pre-activated thiomer of hyaluronic acid is S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-cysteine ​​disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-homocysteine ​​disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-cysteamine disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-N-acetylcysteine ​​disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-thioglycolic acid disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-3-thiopropionic acid disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-4-thiobutanoic acid disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-mercaptobenzoic acid disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-mercaptonicotinic acid disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-glutathione disulfide, and S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-mercaptoaniline disulfide; wherein the side chains are independently attached to the hyaluronic acid backbone via amide or ester bonds.

[0023] In one embodiment, the pre-activated thiomer of hyaluronic acid contains 10 μmol to 1350 μmol, preferably 100 μmol to 1350 μmol, of the mercaptonicotinic acid, mercaptonicotinamide, mercaptoisonicotinamide or mercaptopyridoxine moiety per gram of polymer.

[0024] In one embodiment, the ocular delivery system further comprises a non-preactivated thiomer, preferably a non-preactivated thiomer of hyaluronic acid. In one embodiment, the non-preactivated thiomer is selected from a polymeric compound having a hyaluronic acid backbone with covalently bound thiolated side chains selected from cysteine, homocysteine, N-acetylcysteine, cysteine ​​ethyl ester, cysteamine, mercaptoaniline, adipic acid dihydrazide that are thiolated by reaction with iminothiolane, 5,5'-dithiobis(2-nitrobenzoic acid), dithiobis(propanoic acid dihydrazide), dithiobis(butyric acid dihydrazide), 3-(2-pyridyldithio)propionyl hydrazide, dithiothreitol, ethylene sulfide, thioglycolic acid, 3-thiopropionic acid, 4-thiobutanoic acid, mercaptobenzoic acid, mercaptonicotinic acid, glutathione, and gamma-thiobutyrolactone, wherein the side chains are independently attached to the hyaluronic acid backbone via amide, ether, or ester bonds.

[0025] In one embodiment, the pre-activated thiomers of hyaluronic acid and / or the non-pre-activated thiomers, if present, are cross-linked.

[0026] In one embodiment, the antiglaucoma drug is an intraocular pressure (IOP) lowering drug selected from prostaglandin analogs, cholinergic agents, beta-blockers, alpha-adrenergic agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, NO donors, and combinations thereof. In one embodiment, the antiglaucoma drug is selected from latanoprost, bimatoprost, travoprost, tafluprost, latanoprost bunod, pilocarpine, echothiophate, carbachol, timolol, nadolol, carteolol, levobunolol, metipranolol, betaxolol, brimonidine, apraclonidine, dorzolamide, brinzolamide, acetazolamide, methazolamide, and netarsudil. In one embodiment, the ocular delivery system comprises two antiglaucoma drugs, one of which is a prostaglandin analog and the other of which is a beta-blocker, preferably bimatoprost and timolol.

[0027] In one embodiment, the ocular delivery system further comprises one or more pharma- ceutically acceptable excipients. In one embodiment, the excipients are selected from thickeners, gelling agents, plasticizers, solubilizers, stabilizers, permeation enhancers, diluents, binders, glidants, channeling agents, lubricants, and modified release agents. In one embodiment, the excipients are high molecular weight cross-linked polyacrylic acid polymers, polyvinyl alcohol, polyvinylpyrrolidone (also called povidone), cellulose, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (also called hypromellose), carboxymethyl cellulose, polyethylene glycol, hyaluronic acid, glycerol, cyclodextrin, reduced glutathione, sorbitol, trehalose, xylitol, mannitol, sugars and derivatives thereof, sucrose, lactose, polysaccharides and derivatives thereof, stearic acid malate, glycerol, glycerol, cyclodextrin, glycerol ... In one embodiment, the additives are selected from calcium carbonate, dibasic calcium phosphate, colloidal silicon dioxide, sodium chloride, polyoxyethylene stearate, lauryl sulfate, hydrogenated coco monoglycerides, hydrogenated coco monoglycerides diglycerides and hydrogenated coco monoglycerides triglycerides, glyceryl behenate, stearic acid, glyceryl palmitostearate, glyceryl dibehenate, glyceryl distearate, ammonium methacrylate copolymer (Type A), polyvinyl acetate-povidone copolymer, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0028] In one embodiment, the ocular delivery system comprises: - 0.01% to 50% by weight (w / w) of one or more anti-glaucoma drugs of the total weight of the delivery system; - 5% to 80% w / w of at least one preactivated thiomer of hyaluronic acid; - 0% to 89.99% w / w of non-preactivated thiomers of hyaluronic acid; and - 0% to 94.99% w / w of one or more pharma- ceutically acceptable excipients Includes.

[0029] The present invention also provides an ocular delivery system as defined herein for use in the treatment of glaucoma in a subject in need thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] definition In the present invention, the following terms have the following meanings.

[0031] "Administration" or variations thereof (e.g., "administering") means providing an active agent, either alone or as part of a pharma- ceutically acceptable formulation, to a patient whose condition, symptom, or disease is to be treated.

[0032] "Anti-glaucoma drugs" refer to drugs used to treat glaucoma.

[0033] "Carbomer" refers to a synthetic high molecular weight polyacrylic acid crosslinked with allyl sucrose or allyl pentaerythritol. Examples of carbomers include Carbopol 971 and 974, which are polyacrylic acids crosslinked with allyl pentaerythritol and polymerized in ethyl acetate.

[0034] "Electrospinning" refers to the process of producing a network of three-dimensional polymer nanofibers. Electrospinning uses an electric charge to draw very fine fibers from a liquid. Methods for performing electrospinning are known to those skilled in the art.

[0035] "Human" refers to subjects of both sexes and at any stage of development (i.e., neonate, infant, juvenile, adolescent, adult).

[0036] "Mucooadhesive" refers to the force of attraction between a substance or material and mucus or mucosa. In the context of the present invention, a mucoadhesive ocular delivery system is an ocular delivery system that strongly interacts with the mucus or mucosa of the eye. In a preferred embodiment, the ocular delivery system of the present invention is covalently bound to the mucus or mucosa by the formation of a disulfide bond between the thiomer and the native mucin present therein. This disulfide bond formation is facilitated by the use of a pre-activated thiomer.

[0037] "Nanofibers" refers to fibers having an average diameter of less than 5000 nm, preferably less than 1000 nm.

[0038] "Ocular delivery system" refers to a delivery system that allows for administration of an active pharmaceutical ingredient or substance of interest, such as, for example, an anti-glaucoma drug, to a subject via the eye or any part thereof. "Solid or semi-solid ocular delivery system" refers to solid or semi-solid dosage forms, including ocular inserts and ocular films. In particular, "semi-solid" refers to dosage forms that may be highly viscous, such as ocular inserts in the form of hydrogels.

[0039] "Ophthalmic film" refers to a solid or semi-solid, robust, two-dimensional film designed to be placed in the conjunctival sac or on the conjunctival surface, the size and shape of which are specifically designed for ophthalmic use. Preferably, the ophthalmic film is sterile. The ophthalmic film can be folded to form a three-dimensional device, which can be useful, for example, to facilitate placement of the film on the eye.

[0040] "Ocular insert" refers to a solid or semi-solid, robust, three-dimensional device designed to be placed in the conjunctival sac or on the conjunctival surface, the size and shape of which are specifically designed for ophthalmic use. Preferably, the ocular insert is sterile. Optionally, the ocular insert may be multi-layered. The ocular insert may be in a dry or hydrated form. In the latter case, in the present invention, the ocular insert is preferably in the form of a hydrogel pellet.

[0041] "Ophthalmic condition" refers to any condition affecting any area of ​​the eye and eyelid. Examples of ophthalmic conditions include post-ophthalmic surgery ophthalmic conditions, dry eye conditions, and seasonal allergy ophthalmic conditions.

[0042] "Pharmaceutically acceptable" refers to components of a pharmaceutical formulation that are compatible with each other and not harmful to a subject to which they are administered.

[0043] "Pharmaceutically acceptable excipient" refers to a substance that does not cause adverse, allergic or other untoward reactions when administered to animals, preferably humans. It includes any and all inert substances, such as, for example, solvents, cosolvents, antioxidants, surfactants, stabilizers, emulsifiers, pH adjusters, preserving agents (or preserving agents), antibacterial and antifungal agents, isotonicity agents, granulating or binding agents, lubricants, glidants, diluents or fillers, adsorbents, dispersing agents, suspending agents, coating agents, bulking agents, release agents, absorption retarding agents, sweeteners, flavoring agents, etc. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards required by regulatory authorities, such as, for example, the FDA office or EMA.

[0044] "Polycarbophil" refers to a synthetic polymer made from the crosslinking of polyacrylic acid with divinyl glycol and calcium counterions.

[0045] A "polymeric compound" refers to a polymer. In the sense of the present invention, a polymeric compound may comprise a "polymer backbone" having "side chains".

[0046] "Subject" refers to a mammal, including humans and animals, preferably a human. In one embodiment, the subject is diagnosed with a disease. In one embodiment, the subject is a "patient" awaiting or undergoing medical treatment, or has been / is / will be the subject of medical treatment, or is being monitored for the onset or progression of a disease. In one embodiment, the subject is male. In another embodiment, the subject is female. In one embodiment, the subject is an adult. In another embodiment, the subject is a child.

[0047] A "therapeutically effective amount" or "effective amount" or "therapeutically effective dose" refers to an amount or dose of an active agent intended to (1) delay or prevent the onset of a disease in a subject; (2) reduce the severity or incidence of a disease; (3) slow or halt the progression, severity, or worsening of one or more symptoms of a disease affecting a subject; (4) bring about an improvement in the symptoms of a disease affecting a subject; or (5) treat a disease affecting a subject, without causing significant negative or harmful side effects to the subject. A therapeutically effective amount may be administered prior to the onset of a disease for a prophylactic or preventive action. Alternatively, or additionally, a therapeutically effective amount may be administered after the onset of a disease for a therapeutic action.

[0048] "Treating" or "treatment" refers to both therapeutic and prophylactic or preventative treatments, the purpose being to prevent or alleviate (reduce) the targeted pathological condition or disorder. Those in need of treatment include those already with the disorder, as well as those susceptible to developing the disorder or in whom the disorder is to be prevented. A subject is successfully "treated" for a disease or condition if, after receiving a therapeutic amount of the therapeutic agent, the subject exhibits an observable and / or measurable decrease or absence of one or more of the following: alleviation, to some extent, of one or more symptoms associated with the particular disease or condition, and improvement in quality of life issues. The above parameters for assessing the success of treatment and improvement of a disease are readily measurable by routine means familiar to physicians.

[0049] "Thiomer" or "non-preactivated thiomer" refers to a thiolated polymer, i.e., a polymer having side chains with free thiol moieties (i.e., "thiolated side chains") linked to the polymer backbone. The polymer backbone can be a biodegradable polymer, such as, for example, hyaluronic acid. Thiolation of the polymer backbone can be achieved, for example, by coupling cysteine ​​or cysteamine moieties. "Thiomer of hyaluronic acid" refers to a thiomer in which the polymer backbone is hyaluronic acid.

[0050] "Preactivated thiomer" or "S-protected thiomer" refers to a thiomer in which the thiol moiety of the side chain is conjugated via a disulfide bond with a vitamin B derivative, such as mercaptonicotinic acid, mercapto(iso)nicotinamide, or mercaptopyridoxine. As detailed below, the preactivated thiomer can be obtained by coupling a vitamin B derivative to the free thiol of the thiomer by formation of a disulfide bond, or by direct coupling of a vitamin B derivative-disulfide group-containing side chain onto the polymer backbone. "Preactivated thiomer of hyaluronic acid" refers to a preactivated thiomer in which the polymer backbone is hyaluronic acid.

[0051] "Thiomeric matrix" refers to a matrix made primarily of thiomers (pre-activated and / or not pre-activated).

[0052] Detailed Description Ocular delivery system for antiglaucoma drugs The present invention therefore relates to an ocular drug delivery system useful for the treatment of glaucoma. In particular, the present invention provides a solid or semi-solid delivery system that allows for the efficient delivery of anti-glaucoma drugs at the ocular level. The drug delivery system of the present invention can be an ocular insert or an ocular film. The ocular delivery system of the present invention exhibits mucoadhesive properties that allow the delivery system to remain on the ocular surface for extended periods of time. The mucoadhesive properties are achieved by the presence of at least one pre-activated thiomer of hyaluronic acid in the delivery system. Once hydrated, the thiomer matrix of the ocular delivery system of the present invention forms a hydrogel that adheres to the eye.

[0053] Thus, the present invention provides a mucoadhesive solid or semi-solid ocular delivery system comprising one or more anti-glaucoma drugs in a matrix of a pre-activated thiomer of hyaluronic acid.

[0054] In one embodiment, the ocular delivery system of the present invention comprises: - 1 or more antiglaucoma medications; and at least one preactivated thiomer of hyaluronic acid Includes.

[0055] Antiglaucoma drugs The ocular drug delivery system of the present invention is useful for the treatment of glaucoma by enabling efficient delivery of anti-glaucoma drugs at the ocular level. The ocular drug delivery system of the present invention comprises at least one anti-glaucoma drug.

[0056] In one embodiment, the anti-glaucoma drug is selected from intraocular pressure (IOP) lowering agents. IOP lowering agents can reduce aqueous humor secretion and / or increase aqueous humor drainage from the eye. Examples of IOP lowering agents include prostaglandin analogs, cholinergic agents, beta-blockers, alpha-adrenergic agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, and NO donors. IOP lowering agents that reduce aqueous humor secretion include beta-blockers, carbonic anhydrase inhibitors, and alpha-adrenergic agonists. IOP lowering agents that increase aqueous humor drainage include prostaglandin analogs, cholinergic agents.

[0057] Examples of prostaglandin analogs include latanoprost, bimatoprost, travoprost, tafluprost, and latanoprostene bunod. Examples of cholinergic agonists include pilocarpine, echothiophate, and carbachol. Examples of beta blockers include timolol, nadolol, carteolol, levobunolol, metipranolol, and betaxolol. Examples of alpha adrenergic agonists include brimonidine and apraclonidine. Examples of carbonic anhydrase inhibitors include dorzolamide, brinzolamide, acetazolamide, and methazolamide. Examples of Rho kinase inhibitors include netarsudil. Examples of NO donors include latanoprostene bunod.

[0058] In one embodiment, the ocular drug delivery system of the present invention comprises one or more anti-glaucoma agents selected from latanoprost, bimatoprost, travoprost, tafluprost, latanoprost bunod, pilocarpine, echothiophate, carbachol, timolol, nadolol, carteolol, levobunolol, metipranolol, betaxolol, brimonidine, apraclonidine, dorzolamide, brinzolamide, acetalozamide, methazolamide, and netarsudil.

[0059] In one embodiment, the ocular drug delivery system of the present invention comprises one or more anti-glaucoma drugs. In one embodiment, the ocular drug delivery system of the present invention comprises one anti-glaucoma drug. In one embodiment, the ocular drug delivery system of the present invention comprises two or more anti-glaucoma drugs. In one embodiment, a combination of two or more IOP-lowering drugs is used, preferably a combination of drugs belonging to at least two different classes of IOP-lowering drugs.

[0060] In one embodiment, the ocular drug delivery system of the present invention comprises at least one prostaglandin analog, preferably selected from latanoprost, bimatoprost, travoprost, tafluprost, latanoprost bunod and combinations thereof. In a particular embodiment, the ocular delivery system of the present invention comprises bimatoprost.

[0061] In one embodiment, the ocular drug delivery system of the present invention comprises at least one beta blocker, preferably selected from timolol, nadolol, carteolol, levobunolol, metipranolol, betaxolol, and combinations thereof. In a particular embodiment, the ocular delivery system of the present invention comprises timolol.

[0062] In one embodiment, the ocular drug delivery system of the present invention comprises at least one prostaglandin analog and at least one beta-blocker. In one embodiment, the ocular drug delivery system of the present invention comprises at least one prostaglandin analog selected from latanoprost, bimatoprost, travoprost, tafluprost, latanoprost bunod and at least one beta-blocker selected from timolol, nadolol, carteolol, levobunolol, metipranolol and betaxolol. In one embodiment, the ocular drug delivery system of the present invention comprises bimatoprost and timolol.

[0063] In one embodiment, the ocular drug delivery system of the present invention comprises at least one carbonic anhydrase inhibitor, preferably selected from dorzolamide, brinzolamide, acetazolamide, methazolamide, and combinations thereof.

[0064] In one embodiment, the ocular drug delivery system of the present invention comprises at least one prostaglandin analog and at least one carbonic anhydrase inhibitor. In one embodiment, the ocular drug delivery system of the present invention comprises at least one prostaglandin analog selected from latanoprost, bimatoprost, travoprost, tafluprost, and latanoprost bunod, and at least one carbonic anhydrase inhibitor selected from dorzolamide, brinzolamide, acetazolamide, and methazolamide.

[0065] In one embodiment, the ocular drug delivery system of the present invention comprises at least one alpha adrenergic agonist, preferably selected from brimonidine, apraclonidine, and combinations thereof.

[0066] In one embodiment, the ocular drug delivery system of the present invention comprises at least one prostaglandin analog and at least one alpha adrenergic agonist. In one embodiment, the ocular drug delivery system of the present invention comprises at least one prostaglandin analog selected from latanoprost, bimatoprost, travoprost, tafluprost, and latanoprost bunod, and at least one alpha adrenergic agonist selected from brimonidine and apraclonidine.

[0067] According to one embodiment, the ocular delivery system of the present invention comprises one or more anti-glaucoma drug(s) in an amount ranging from 0.01% to 50% by weight of the total weight of the delivery system, preferably from 0.1% w / w to 20% w / w, more preferably from 0.1% w / w to 10% w / w, more preferably from 0.1% w / w to 5% w / w.

[0068] In one embodiment, the ocular delivery system of the present invention comprises one or more anti-glaucoma drugs and at least one supplemental pharmacologic active. The supplemental pharmacologic active may be selected from, for example, anti-inflammatory agents and dry eye treatments. Preferably, the supplemental pharmacologic active is an ophthalmic drug.

[0069] Examples of anti-inflammatory agents include corticosteroid anti-inflammatory agents (dexamethasone, fluorometholone, rimexolone, fluocinolone, fluticasone, loteprednol) and nonsteroidal anti-inflammatory agents (bromfenac sesquihydrate, amfenac, nepafenac, aspirin, ibuprofen, ketorolac, tramethamine, diclofenac, flurbiprofen). Examples of dry eye treatments include immunosuppressants such as cyclosporine or tacrolimus.

[0070] According to further embodiments, the ocular delivery system of the present invention also allows for the delivery of other active agents, including relief agents for ocular conditions such as dry eye. Examples of such relief agents include lubricants such as polyvinyl acid (PVA) or polyvinylpyrrolidone (PVP, also known as povidone).

[0071] Preactivated thiomers of hyaluronic acid The ocular delivery system of the present invention comprises at least one preactivated thiomer of hyaluronic acid. The presence of the preactivated thiomer of hyaluronic acid in the delivery system of the present invention gives the system mucoadhesive properties, making it possible to achieve the expected delivery properties, preferably a release rate longer than 2 days, more preferably a release rate longer than 3 days. Furthermore, the presence of the preactivated thiomer of hyaluronic acid in the insert induces swelling and gel formation upon hydration. The use of hyaluronic acid as the backbone of the preactivated thiomer is advantageous in terms of ocular tolerance, hydration and lubricity, as well as gelling properties. Hyaluronic acid is known to be well adapted for ocular use.

[0072] In the ocular delivery system of the invention, the preactivated thiomers of hyaluronic acid form a matrix that makes it possible to form an insert or film with mucoadhesive properties, which also makes it possible to carry anti-glaucoma drugs and deliver them at the ocular level.

[0073] Hyaluronic acid (HA) is a linear polysaccharide whose basic structure consists of repeating disaccharide units, namely D-glucuronic acid and N-acetylglucosamine, linked by β(1,4) and β(1,3) glycosidic bonds. [ka]

[0074] A preactivated thiomer is a polymeric compound with a side chain containing a vitamin B derivative-disulfide group, said side chain being covalently bonded to the polymer backbone.Therefore, "preactivated thiomer of hyaluronic acid" refers to hyaluronic acid modified by the presence of a side chain containing a vitamin B derivative-disulfide group, preferably a side chain containing a group selected from a (iso)nicotinic acid-disulfide group, a (iso)nicotinamide-disulfide group and a mercaptopyridoxine-disulfide group, in particular a 2-nicotinic acid-disulfide group, a 6-nicotinic acid-disulfide group, a 2-nicotinamide-disulfide group, a 2-isonicotinamide-disulfide group, a 6-nicotinamide-disulfide group, a 6-isonicotinamide-disulfide group and a 6-pyridoxine-disulfide group.

[0075] As used herein, the group "2-nicotinic acid-disulfide" refers to the following group: [ka] This defines 6-nicotinic acid disulfide group, 2-nicotinamide disulfide group, 2-isonicotinamide disulfide group, 6-nicotinamide disulfide group, 6-isonicotinamide disulfide group, and 6-pyridoxine disulfide group.

[0076] The preactivated thiomers of hyaluronic acid can be obtained by two synthetic routes: (a) a two-step synthesis or (b) a one-step synthesis.

[0077] In the two-step synthesis (a), the hyaluronic acid backbone is first modified by covalent bonding of a ligand containing a free thiol group (step a1), leading to a hyaluronic acid thiomer. In the second step (step a2), the previously introduced free thiol group of the side chain is preactivated by disulfide bond formation with a vitamin B derivative, leading to a preactivated hyaluronic acid thiomer.

[0078] "Thiomers of hyaluronic acid" or "thiolated hyaluronic acid" refers to hyaluronic acid to which a ligand containing a free thiol group as a side chain is covalently attached onto its backbone. Two chemical groups of HA, the carboxylic acid and the hydroxyl groups, can be modified to form thiolated HA via different reactions, such as amidation on the carboxylic acid or ether or ester formation on the hydroxyl groups. Examples of ligands that can be used to form thiolated HA by amidation of the carboxylic acid include cysteine, homocysteine, N-acetylcysteine, cysteine ​​ethyl ester, cysteamine, mercaptoaniline, adipic acid dihydrazide (ADH), which are thiolated by reaction with Traut's reagent (iminothiolane), 5,5'-dithiobis(2-nitrobenzoic acid), dithiobis(propanoic acid dihydrazide), dithiobis(butyric acid dihydrazide), 3-(2-pyridyldithio)propionyl hydrazide, and dithiothreitol. Examples of ligands that can be used to form thiolated HA by ether formation on the hydroxyl groups include ethylene sulfide. Examples of ligands that can be used to form thiolated HA by ester formation on the hydroxyl groups include thioglycolic acid, 3-thiopropionic acid, 4-thiobutanoic acid, mercaptobenzoic acid, mercaptonicotinic acid, glutathione, and gamma-thiobutyrolactone.

[0079] As an example of the two-step synthesis (a), the scheme below shows the amidation (step a1) with an aminothiol ligand (which can be, for example, cysteine ​​or cysteamine) to form thiolated HA, followed by thiolation of the carboxylic acid groups of HA by protection of the free thiol groups via preactivation with 6-mercaptonicotinamide. [ka]

[0080] Thus, the synthesis of the pre-activated thiomer of hyaluronic acid can be carried out by reacting a thiolated hyaluronic acid backbone with 2-mercaptonicotinic acid, 6-mercaptonicotinic acid, 2-mercaptonicotinamide, 2-mercaptoisonicotinamide, 6-mercaptoisonicotinamide, 6,6'-dithionicotinamide or 6-mercaptopyridoxine.In one embodiment, the pre-activated thiomer of hyaluronic acid used in the ocular delivery system of the present invention is prepared according to the method disclosed in U.S. Patent Publication No. 2012 / 0225024.

[0081] In one embodiment, the pre-activated thiomer of hyaluronic acid is selected from polymeric compounds having 2-mercaptonicotinic acid, 6-mercaptonicotinic acid, 2-mercaptonicotinamide, 2-mercaptoisonicotinamide, 6-mercaptoisonicotinamide, 6-mercaptoisonicotinamide, or 6-mercaptopyridoxine side chains covalently attached to a thiolated hyaluronic acid backbone via disulfide bonds.

[0082] In an alternative synthetic route, the one-step synthesis (b), the hyaluronan backbone is directly modified by covalent attachment of a vitamin B derivative-disulfide group-containing ligand, leading to a preactivated thiomer of hyaluronan.

[0083] As an example of a one-step synthesis (b), the scheme below shows the modification of the carboxylic acid groups of HA by amidation with (6-nicotinic acid)-disulfide amino ligands (e.g., S-(6-mercaptonicotinic acid)-cysteine ​​disulfide or S-(6-nicotinic acid)-cysteamine disulfide) to form the corresponding pre-activated thiomer of HA. [ka]

[0084] Therefore, the synthesis of preactivated thiomers of hyaluronic acid can be carried out by reacting hyaluronic acid with a vitamin B derivative-ligand containing a disulfide group. Such disulfide ligands include: - one vitamin B derivative, such as 2-mercaptonicotinic acid (2-MNA), 6-mercaptonicotinic acid (6-MNA), 2-mercaptonicotinamide (2-MNamide), 2-mercaptoisonicotinamide, 6-mercaptonicotinamide (6-MNamide), 6-mercaptoisonicotinamide or 6-mercaptopyridoxine; and - cysteine, homocysteine, N-acetylcysteine, cysteine ​​ethyl ester, cysteamine, mercaptoaniline, adipic dihydrazide (ADH), which are thiolated by reaction with one thiolated ligand, such as Traut's reagent (iminothiolane), 5,5'-dithiobis(2-nitrobenzoic acid), dithiobis(propanoic acid dihydrazide), dithiobis(butyric acid dihydrazide), 3-(2-pyridyldithio)propionyl hydrazide, dithiothreitol, ethylene sulfide, thioglycolic acid, 3-thiopropionic acid, 4-thiobutanoic acid, mercaptobenzoic acid, mercaptonicotinic acid, and glutathione. It may be a disulfide adduct made from

[0085] In one embodiment, the disulfide ligand used in the one-step synthesis (b) to form the pre-activated thiomer of hyaluronic acid is -2-((2-aminoethyl)disulfanayl)nicotinic acid (i.e., 2-MNA / cysteamine); -6-((2-aminoethyl)disulfanayl)nicotinic acid (i.e., 6-MNA / cysteamine); -2-((2-amino-2-carboxyethyl)disulfanayl)nicotinic acid (i.e., 2-MNA / cysteine); -6-((2-amino-2-carboxyethyl)disulfanayl)nicotinic acid (i.e., 6-MNA / cysteine); -2-((2-aminoethyl)disulfanayl)nicotinamide (i.e., 2-MNamide / cysteamine); -6-((2-aminoethyl)disulfanayl)nicotinamide (i.e., 6-MNamide / cysteamine); S-(3-carbamoylpyridin-2-yl)thio)cysteine ​​(i.e., 2-MNamide / cysteine); and -S-(5-carbamoylpyridin-2-yl)thio)cysteine ​​(i.e., 6-MNamide / cysteine) is selected from.

[0086] Regardless of the method of synthesis, the disulfide side chains of the preactivated thiomers of hyaluronan are S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-cysteine ​​disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-homocysteine ​​disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-cysteamine disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-N-acetylcysteine ​​disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-thioglycolic acid disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-3-thiopropionic acid disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-4-thiobutanoic acid disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-mercaptobenzoic acid disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-mercaptonicotinic acid disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-glutathione disulfide, and S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-mercaptoaniline disulfide wherein the side chains are independently attached to the hyaluronic acid backbone via amide or ester bonds.

[0087] As used herein, S-(2- or 6-mercaptonicotinic acid) is defined to represent S-(2-mercaptonicotinic acid)- or S-(6-mercaptonicotinic acid)-; S-(2- or 6-mercapto(iso)nicotinamide) is defined to represent S-(2-mercaptonicotinamide)-, S-(2-mercaptoisonicotinamide-, S-(6-mercaptonicotinamide)-, or S-(6-mercaptoisonicotinamide)-.

[0088] The mucoadhesive properties of the preactivated thiomer can be adjusted by adjusting the degree of functionalization of the hyaluronic acid backbone with vitamin B derivative-disulfide side chains. Moreover, it has been shown that increasing the degree of functionalization advantageously allows the amount of preactivated thiomer used in the delivery system to be reduced while maintaining the mucoadhesive properties. In one embodiment, the preactivated thiomer of hyaluronic acid comprises 10 μmol to 1350 μmol per gram of polymer, preferably 10 μmol to 1000 μmol per gram of polymer, preferably 50 μmol to 500 μmol per gram of polymer, more preferably 50 μmol to 200 μmol per gram of polymer of the moiety of mercaptonicotinic acid, mercaptonicotinamide, mercaptoisonicotinamide or mercaptopyridoxine. In one embodiment, the pre-activated thiomer of hyaluronic acid comprises 10 μmol to 1350 μmol per gram of polymer, preferably 100 μmol to 1350 μmol per gram of polymer, preferably 150 μmol to 1350 μmol per gram of polymer, more preferably 200 μmol to 1350 μmol per gram of polymer.

[0089] The viscosity of the preactivated thiomer can be adjusted by varying the molecular weight of the polymer. The molecular weight of the hyaluronic acid backbone also influences its degree of functionalization. In particular, it has been observed that the degree of functionalization tends to decrease with increasing molecular weight, thereby affecting mucoadhesion. Furthermore, the molecular weight of the polymer influences the swelling of the delivery system of the present invention: swelling increases with molecular weight. Preferably, preactivated thiomers of hyaluronic acid with a medium molecular weight are used, with a molecular weight in the range of 100 kDa to 1200 kDa, preferably 100 kDa to 1000 kDa, more preferably 200 kDa to 800 kDa. In one embodiment, the preactivated thiomers of hyaluronic acid have a molecular weight in the range of 100 kDa to 1200 kDa, preferably 200 kDa to 1200 kDa.

[0090] In one embodiment, the pre-activated thiomer of hyaluronic acid does not contain free thiol groups. The absence of free thiol groups can be achieved by the one-step route of synthesis (b) above, or by using the two-step method (a) to prepare the pre-activated thiomer, and step (a2) is carried out under conditions such that all free thiols of the thiolated backbone are pre-activated.

[0091] In another embodiment, the preactivated thiomer of hyaluronic acid comprises preactivated disulfide side chains and free thiol side chains. The free thiol side chains may be present when the preactivated thiomer of hyaluronic acid is obtained by the above two-step method (a), in which the first thiolation of the HA backbone is followed by preactivation of a fraction of the free thiol groups. The free thiol side chains are those that form the thiolated hyaluronic acid backbone before preactivation. The free thiol side chains can be selected from cysteine, homocysteine, N-acetylcysteine, cysteine ​​ethyl ester, cysteamine, mercaptoaniline, adipic acid dihydrazide (ADH) which are thiolated by reaction with Traut's reagent (iminothiolane), 5,5'-dithiobis(2-nitrobenzoic acid), dithiobis(propanoic acid dihydrazide), dithiobis(butyric acid dihydrazide), 3-(2-pyridyldithio)propionyl hydrazide, dithiothreitol, ethylene sulfide, thioglycolic acid, 3-thiopropionic acid, 4-thiobutanoic acid, mercaptobenzoic acid, mercaptonicotinic acid, glutathione, and gamma thiobutyrolactone. The amount of remaining free thiol side chains can be controlled by varying the amount of vitamin B derivative added during step (a2).

[0092] The presence of free thiol groups in the preactivated thiomer of hyaluronic acid can affect the gelation rate of the ocular system due to the presence of free thiol groups that promote the formation of gels upon hydration.The presence of free thiol groups can also lead to crosslinking of the thiomer matrix.The crosslinking of the thiomer matrix can be controlled by the ratio of free thiol groups, which in turn can control the cohesiveness of the gel that is formed upon hydration.

[0093] In one embodiment, the preactivated thiomer of hyaluronic acid is partially crosslinked through the formation of disulfide bonds. Crosslinking can occur when the preactivated thiomer of hyaluronic acid contains free thiol groups. In such cases, crosslinking can occur (i) within one single polymer chain between different free thiol groups present on the side chains; (ii) between two chains of preactivated thiomers containing free thiol groups; or (iii) between the preactivated thiomer of hyaluronic acid containing free thiol groups and another species present in the ocular system containing free thiol groups. Case (iii) can occur, for example, when the ocular system of the present invention also contains a non-preactivated thiomer, as described in detail below. Alternatively, crosslinking can occur when the preactivated thiomer of hyaluronic acid does not contain free thiol groups, but the ocular system of the present invention also contains a species containing free thiol groups, such as a non-preactivated thiomer, which can induce S-deprotection in the preactivated thiomer.

[0094] The degree of crosslinking of the thiomeric matrix of the ophthalmic system of the present invention affects the cohesiveness of the gel formed upon hydration. Cohesiveness is an important property of the ophthalmic system of the present invention since it affects the physical integrity of the gel over time, which in turn affects the drug release profile. Indeed, the more cohesive the system is, the longer it remains on the eye, thereby extending the drug release profile. Cohesiveness can be examined by rheological measurements (storage and loss moduli, dynamic viscoelasticity, etc.) and by evaluating the swelling of the system upon water absorption after hydration.

[0095] In one embodiment, the preactivated thiomer of hyaluronic acid present in the ocular delivery system of the invention is in the form of nanofibers, preferably obtained by electrospinning, which presents the advantage of making it possible to control the release rate of the antiglaucoma drug present in the delivery system by varying the density of the nanofiber network.

[0096] According to one embodiment, the ocular delivery system of the present invention comprises at least one pre-activated thiomer of hyaluronic acid in an amount ranging from 5% to 99.99% by weight (w / w), preferably from 10% to 99.99% by weight (w / w) of the total weight of the delivery system. In another embodiment, the ocular delivery system of the present invention comprises at least one pre-activated thiomer of hyaluronic acid in an amount ranging from 5% to 99.99% by weight (w / w), preferably from 5% to 80% by weight (w / w), more preferably from 5% to 50% by weight (w / w), more preferably from 5% to 30% by weight (w / w), more preferably from 5% to 25% by weight (w / w) of the total weight of the delivery system.

[0097] According to one embodiment, the ocular delivery system of the present invention further comprises, in addition to at least one pre-activated thiomer of hyaluronic acid, one or more other pre-activated thiomers in which the polymer backbone is other than hyaluronic acid.

[0098] Non-preactivated thiomer In one embodiment, the ocular delivery system of the present invention further comprises a thiomer that is not preactivated, ie, a thiomer.

[0099] In a preferred embodiment, the non-preactivated thiomer is a thiomer of hyaluronic acid.

[0100] According to one embodiment, the thiolation of the hyaluronic acid backbone can be carried out by coupling, via an amide, ether or ester bond, a moiety selected from cysteine, homocysteine, N-acetylcysteine, cysteine ​​ethyl ester, cysteamine, mercaptoaniline, adipic acid dihydrazide (ADH), which is thiolated by reaction with Traut's reagent (iminothiolane), 5,5'-dithiobis(2-nitrobenzoic acid), dithiobis(propanoic acid dihydrazide), dithiobis(butyric acid dihydrazide), 3-(2-pyridyldithio)propionylhydrazide, dithiothreitol, ethylene sulfide, thioglycolic acid, 3-thiopropionic acid, 4-thiobutanoic acid, mercaptobenzoic acid, mercaptonicotinic acid, glutathione and gamma thiobutyrolactone.Preferably, the thiolation of the polymer backbone is carried out by coupling cysteine ​​or cysteamine.

[0101] In one embodiment, the non-preactivated thiomer, preferably the thiomer of hyaluronic acid, contains 100 μmol to 1500 μmol of thiol groups per gram of polymer, preferably 100 μmol to 800 μmol per gram of polymer, preferably 200 μmol to 800 μmol per gram of polymer.

[0102] In one embodiment, the non-preactivated thiomer present in the ocular delivery system of the present invention is in the form of nanofibers, preferably nanofibers obtained by electrospinning.

[0103] According to one embodiment, the ocular delivery system of the present invention comprises a non-preactivated thiomer, preferably a thiomer of hyaluronic acid, in an amount ranging from 0% to 89.99% by weight (w / w) of the total weight of the delivery system, preferably 0% to 30% w / w; more preferably 0% to 25% w / w; more preferably 0% to 20% w / w.

[0104] In one embodiment, the presence of non-preactivated thiomers in the ophthalmic systems of the present invention advantageously results in crosslinking of the thiomer matrix, thereby enhancing the cohesiveness and drug release profile of the system.

[0105] Excipients In one embodiment, the ocular delivery system of the present invention comprises an excipient, preferably a pharma- ceutically acceptable excipient. Such suitable excipients will be apparent to those skilled in the art and are referred to in the most recent edition of Remington's Pharmaceutical Sciences.

[0106] According to one embodiment, the ocular delivery system of the present invention comprises one or more pharma- ceutically acceptable excipients selected from thickening agents, gelling agents, plasticizers, solubilizers, stabilizers, permeation enhancers, diluents, binders, glidants, channeling agents, lubricants, and modified release agents.

[0107] Examples of thickening and gelling agents include high molecular weight cross-linked polyacrylic acid polymers (e.g., Carbopol), polyvinyl alcohol, polyvinylpyrrolidone (PVP, also known as povidone), cellulose derivatives (e.g., hydroxypropyl methylcellulose (HPMC; also known as hypromellose), carboxymethylcellulose (CMC), hydroxypropyl cellulose (HPC)), polyethylene glycol (PEG), and hyaluronic acid.

[0108] Examples of plasticizers include glycerol and polyethylene glycol (PEG).

[0109] Examples of solubilizing and stabilizing agents, particularly for active pharmaceutical ingredients, include cyclodextrins and non-ionic surfactants.

[0110] Examples of penetration enhancers include reduced glutathione (GSH; 0.1% to 1% w / w).

[0111] Examples of diluents include sugar alcohols such as sorbitol, trehalose, xylitol or mannitol.

[0112] Examples of binders include sugars and their derivatives; disaccharides, such as sucrose or lactose; polysaccharides and their derivatives, such as starch, cellulose or modified cellulose, such as microcrystalline cellulose and cellulose ethers, such as hydroxypropylcellulose (HPC); sugar alcohols, such as xylitol, sorbitol or mannitol; synthetic polymers, such as polyvinylpyrrolidone (PVP, also called povidone) or polyethylene glycol (PEG).

[0113] Examples of lubricants include magnesium stearate, dibasic calcium phosphate, starch, microcrystalline cellulose and colloidal silicon dioxide.

[0114] Examples of channeling agents include sodium chloride (NaCl) and polyethylene glycol (PEG) of molecular weight between 400 and 1500 g / mol.

[0115] Examples of lubricants include soluble lubricants such as polyethylene glycol (PEG), polyoxyethylene stearate, lauryl sulfate, hydrogenated coco monoglyceride, hydrogenated coco monoglyceride diglyceride, and hydrogenated coco monoglyceride triglyceride (Hard Fat-Witepsol®); and insoluble lubricants such as magnesium stearate, glyceryl behenate, stearic acid, and glyceryl palmitostearate.

[0116] Examples of modified release agents include glyceryl dibehenate, glyceryl distearate, ammonium methacrylate copolymer (Type A), polyvinyl acetate-povidone copolymer (Kollidon® SR), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®).

[0117] According to one embodiment, the ocular delivery system of the present invention comprises a polysaccharide, a saccharide derivative, a saccharide mixture, a saccharide ester, a saccharide sorbitol, a saccharide ester ... The composition includes one or more pharma- ceutically acceptable excipients selected from dibasic calcium phosphate, colloidal silicon dioxide, sodium chloride, polyoxyethylene stearate, lauryl sulfate, hydrogenated coco monoglycerides, hydrogenated coco monoglyceride diglycerides and hydrogenated coco monoglyceride triglycerides, glyceryl behenate, stearic acid, glyceryl palmitostearate, glyceryl dibehenate, glyceryl distearate, ammonium methacrylate copolymer (Type A), polyvinyl acetate-povidone copolymer, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0118] According to one embodiment, the ocular delivery system of the present invention comprises one or more pharma- ceutically acceptable excipients selected from polyvinylpyrrolidone (also called povidone), hydroxypropyl methylcellulose (also called hypromellose), magnesium stearate, glyceryl dibehenate, and mixtures thereof. According to one embodiment, the ocular delivery system of the present invention comprises one or more pharma-ceutically acceptable excipients selected from polyvinylpyrrolidone (also called povidone), hydroxypropyl methylcellulose (also called hypromellose), magnesium stearate, and mixtures thereof.

[0119] According to one embodiment, the ocular delivery system of the present invention comprises one or more pharma- ceutically acceptable excipients in an amount ranging from 0% to 94.99% by weight (w / w), preferably 0% to 94.5% w / w, preferably 0% to 89.99% w / w of the total weight of the delivery system. In one embodiment, the amount of pharma-ceutically acceptable excipient(s) is in the range of 40% to 94.5% w / w.

[0120] The excipients present in the ocular delivery system of the present invention may make it possible to control swelling upon hydration. In fact, it should be avoided that the system acquires excessive volume upon hydration, otherwise it will not be suitable for ocular use. In case of excessive swelling upon hydration, the ocular delivery system from the present invention may be drained from the conjunctival sac. The natural movement of the eyeball combined with the permanent blinking of the eyelids generates a significant shear movement on the ocular delivery system, which in turn significantly reduces the duration of its residence on the ocular surface.

[0121] The excipients present in the ocular delivery systems of the present invention may also make it possible to control the firmness of the ocular delivery system, particularly for systems used in a dry form.

[0122] The selection of excipients present in the ocular delivery systems of the present invention may also make it possible to control the release rate of the active agent present in the delivery system.

[0123] Compositions of Ocular Delivery Systems Thus, the ocular delivery system of the present invention comprises: - 1 or more antiglaucoma medications; and at least one preactivated thiomer of hyaluronic acid selected from polymeric compounds having a hyaluronic acid backbone carrying covalently bound side chains comprising groups selected from 2-nicotinic acid disulfide groups, 6-nicotinic acid disulfide groups, 2-nicotinamide disulfide groups, 2-isonicotinamide disulfide groups, 6-nicotinamide disulfide groups, 6-isonicotinamide disulfide groups, and 6-pyridoxine disulfide groups; Includes.

[0124] Thus, the ocular delivery system of the present invention comprises: - 1 or more antiglaucoma medications; and at least one preactivated thiomer of hyaluronic acid selected from polymeric compounds having a hyaluronic acid backbone with covalently bound side chains comprising groups selected from 2-nicotinic acid disulfide groups, 6-nicotinic acid disulfide groups, 2-nicotinamide disulfide groups, 2-isonicotinamide disulfide groups, 6-nicotinamide disulfide groups, 6-isonicotinamide disulfide groups, and 6-pyridoxine disulfide groups; wherein the pre-activated thiomer of hyaluronic acid has a molecular weight in the range of 100 kDa to 1200 kDa.

[0125] In one embodiment, the ocular delivery system of the present invention comprises: - 1 or more antiglaucoma medications; at least one preactivated thiomer of hyaluronic acid selected from polymeric compounds having a hyaluronic acid backbone with covalently bound side chains comprising groups selected from 2-nicotinic acid disulfide groups, 6-nicotinic acid disulfide groups, 2-nicotinamide disulfide groups, 2-isonicotinamide disulfide groups, 6-nicotinamide disulfide groups, 6-isonicotinamide disulfide groups, and 6-pyridoxine disulfide groups; - optionally a non-preactivated thiomer; and - optionally one or more pharma- ceutically acceptable excipients Includes.

[0126] In one embodiment, the ocular delivery system of the present invention comprises: - 1 or more antiglaucoma medications; at least one preactivated thiomer of hyaluronic acid selected from polymeric compounds having a hyaluronic acid backbone with covalently bound side chains comprising groups selected from 2-nicotinic acid-disulfide groups, 6-nicotinic acid-disulfide groups, 2-nicotinamide-disulfide groups, 2-isonicotinamide-disulfide groups, 6-nicotinamide-disulfide groups, 6-isonicotinamide-disulfide groups, and 6-pyridoxine-disulfide groups, the at least one preactivated thiomer of hyaluronic acid having a molecular weight in the range of 100 kDa to 1200 kDa; - optionally a non-preactivated thiomer; and - optionally one or more pharma- ceutically acceptable excipients Includes.

[0127] In one embodiment, the ocular delivery system of the present invention comprises: - 0.01% to 50% by weight (w / w), preferably 0.1% w / w to 20% w / w, more preferably 0.1% w / w to 10% w / w of one or more anti-glaucoma drugs of the total weight of the delivery system; and - 5% w / w to 99.99% w / w of at least one preactivated thiomer of hyaluronic acid as defined herein Includes.

[0128] In one embodiment, the ocular delivery system of the present invention comprises: - 0.01% to 50% by weight (w / w), preferably 0.1% w / w to 20% w / w, more preferably 0.1% w / w to 10% w / w of one or more anti-glaucoma drugs of the total weight of the delivery system; and - 10% w / w to 99.99% w / w of at least one preactivated thiomer of hyaluronic acid as defined herein Includes.

[0129] In one embodiment, the ocular delivery system of the present invention comprises: - 0.01% to 50% by weight (w / w), preferably 0.1% w / w to 20% w / w, more preferably 0.1% w / w to 10% w / w of one or more anti-glaucoma drugs of the total weight of the delivery system; and - 5% w / w to 80% w / w of at least one preactivated thiomer of hyaluronic acid as defined herein Includes.

[0130] In one embodiment, the ocular delivery system of the present invention comprises: - 0.01% to 50% by weight (w / w), preferably 0.1% w / w to 20% w / w, more preferably 0.1% w / w to 10% w / w of one or more anti-glaucoma drugs of the total weight of the delivery system; - 10% w / w to 99.99% w / w of at least one preactivated thiomer of hyaluronic acid as defined herein; - 0% w / w to 89.99% w / w of preactivated thiomer; and - 0% w / w to 89.99% w / w of one or more pharma- ceutically acceptable excipients Includes.

[0131] In one embodiment, the ocular delivery system of the present invention comprises: - 0.01% to 50% by weight (w / w), preferably 0.1% w / w to 20% w / w, more preferably 0.1% w / w to 10% w / w of one or more anti-glaucoma drugs of the total weight of the delivery system; -5% w / w to 80% w / w of at least one preactivated thiomer of hyaluronic acid as defined herein; - 0% w / w to 89.99% w / w of preactivated thiomer; and - 0% w / w to 94.99% w / w of one or more pharma- ceutically acceptable excipients Includes.

[0132] In one embodiment, the ocular delivery system of the present invention comprises: - 0.1% to 10% by weight (w / w), preferably 0.1% w / w to 5% w / w of one or more anti-glaucoma drugs of the total weight of the delivery system; -5% w / w to 25% w / w of at least one preactivated thiomer of hyaluronic acid as defined herein; - 0% w / w to 25% w / w of preactivated thiomer; and - one or more pharma- ceutically acceptable excipients, from 0% w / w to 94.5% w / w, preferably from 40% w / w to 94.5% w / w Includes.

[0133] In one embodiment, the ocular delivery system of the present invention comprises: - 0.1% to 10% by weight (w / w), preferably 0.1% w / w to 5% w / w of one or more anti-glaucoma drugs of the total weight of the delivery system; -5% w / w to 25% w / w of at least one pre-activated thiomer of hyaluronic acid as defined herein, said pre-activated thiomer having a molecular weight in the range of 100 kDa to 1200 kDa; - 0% w / w to 25% w / w of preactivated thiomer; and - one or more pharma- ceutically acceptable excipients, from 0% w / w to 94.5% w / w, preferably from 40% w / w to 94.5% w / w Includes.

[0134] In one embodiment, the ocular delivery system of the present invention comprises: - 0.1% to 10% by weight (w / w), preferably 0.1% w / w to 5% w / w of one or more anti-glaucoma drugs of the total weight of the delivery system; -5% w / w to 25% w / w of at least one pre-activated thiomer of hyaluronic acid as defined herein, having a molecular weight in the range of 100 kDa to 1200 kDa, preferably 200 kDa to 1200 kDa, and comprising 100 μmol to 1350 μmol per gram of polymer, preferably 150 μmol to 1350 μmol per gram of polymer, preferably 200 μmol to 1350 μmol per gram of polymer of the moiety mercaptonicotinic acid, mercaptonicotinamide, mercaptoisonicotinamide or mercaptopyridoxine; - 0% w / w to 25% w / w of preactivated thiomer; and - one or more pharma- ceutically acceptable excipients, from 0% w / w to 94.5% w / w, preferably from 40% w / w to 94.5% w / w Includes.

[0135] Characteristics of the Ocular Delivery System The ocular delivery system of the present invention exhibits mucoadhesive properties, in particular ocular mucoadhesive properties, i.e. it strongly interacts with mucus or mucosa, in particular ocular mucus or mucosa. The mucoadhesive properties of the ocular delivery system of the present invention can be measured by the rotating cylinder method, as described in the art. The mucoadhesive properties of the ocular delivery system of the present invention make it possible to achieve mucoadhesion for at least 2 days, preferably at least 3 days, more preferably 3-8 days, even more preferably 3-10 days. The mucoadhesive properties can be adjusted by varying the degree of functionalization of the hyaluronic acid backbone with vitamin B derivative-disulfide side chains in the preactivated thiomer of hyaluronic acid used in the system.

[0136] The ocular delivery system of the present invention allows one or more anti-glaucoma drugs present therein to be efficiently released to the subject to which it is administered. Advantageously, the ocular delivery system of the present invention allows one or more anti-glaucoma drugs to be sustained released to the eye. The release of one or more glaucoma drugs can be evaluated by dissolution testing, such as placing the delivery system in water (or in simulated tear fluid) and sampling the solution at different time points to measure the amount of drug released therein. In one embodiment, the one or more anti-glaucoma drugs are released in a therapeutically effective amount in the eye for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days.

[0137] The release profile is influenced by the adhesiveness of the ocular system once hydrated. The more adhesive the system, the longer it remains on the eye, thereby extending the drug release profile. The adhesiveness can be adjusted by the degree of crosslinking of the thiomeric matrix of the system, i.e., the matrix made of preactivated thiomers of hyaluronic acid, and the presence of non-preactivated thiomers.

[0138] After being placed in the conjunctival sac or on the conjunctival surface, the ocular delivery system of the present invention must either completely dissolve during use or be removed after a period of time (e.g., several days). If removal is required, an eyewash can be used for this purpose.

[0139] The ocular delivery system of the present invention can be used in a dry or hydrated form. In one embodiment, the ocular delivery system of the present invention is used in a hydrated form, i.e., the pre-activated thiomer matrix is ​​hydrated in the form of a hydrogel before administration. In another embodiment, the ocular delivery system of the present invention is in a dry form, i.e., it contains limited amounts of water, if any. In such a case, once placed in the conjunctival sac or on the conjunctival surface, the delivery system of the present invention hydrates in situ and the hydrated pre-activated thiomer matrix forms a mucoadhesive hydrogel (i.e., an in situ gelation process).

[0140] In one embodiment, the hydration rate of the ocular delivery system of the present invention ranges from 1 minute to 24 hours, preferably from 1 minute to 1 hour, and more preferably from 1 minute to 30 minutes.

[0141] Upon hydration, the ocular delivery system of the present invention swells. The swelling rate of the ocular delivery system of the present invention needs to be controlled, especially for direct use in dry form. The swelling rate can be measured gravimetrically: (1) weigh the system (W0); (2) it is then immersed in water or in a solvent such as simulated tear fluid; (3) at several time points, the system is removed and the excess water is removed by gently wicking with tissue paper and reweighed (W0). t The water absorption (i.e., swelling ratio in weight percent) is expressed as [(W t-W0) / W0]×100. In one embodiment, the maximum swelling ratio of the ocular delivery system of the present invention once hydrated ranges from 0% to 10000% by weight (w / w), preferably 0% to 5000% by weight, more preferably 0% to 2000% by weight based on the dry form weight. In one embodiment, the maximum swelling ratio of the ocular delivery system of the present invention once hydrated ranges from 100% to 10000% by weight (w / w), preferably 100% to 5000% by weight, more preferably 100% to 2500% by weight, more preferably 100% to 2000% by weight, more preferably 100% to 1500% by weight based on the dry form weight. The swelling ratio depends on several factors including the molecular weight of the preactivated thiomer, the amount of preactivated thiomer present in the system, the degree of crosslinking of the matrix, and the amount of non-preactivated thiomer present in the system. The size of the system and its stiffness (especially when used in the form of an insert) also affect the swelling ratio.

[0142] The ocular delivery systems of the present invention may also be characterized by their "residence period" (or "period of residence"), i.e., the period of presence of the ocular delivery system at the eye level, particularly in the lower conjunctival sac. The residence period of the ocular delivery systems of the present invention may be measured by in vivo assays. The residence period of the ocular delivery systems of the present invention is preferably at least 2 days, more preferably at least 3 days, and even more preferably 3 to 10 days. The residence period depends on several factors, including the size and shape of the system, its mucoadhesiveness, its cohesiveness, its erosion, and its swelling behavior. These parameters may be influenced by the composition of the delivery system.

[0143] The solid or semi-solid ocular delivery systems of the present invention can be ocular inserts or ocular films.

[0144] In one embodiment, the solid or semi-solid ocular delivery system of the present invention is an ocular insert, i.e., a solid or semi-solid, robust, three-dimensional device designed to be placed in the conjunctival sac or on the conjunctival surface, the size and shape of which are specifically designed for ophthalmic use. In one embodiment, the ocular insert is in a dry form. In another embodiment, the ocular insert is hydrated and in the form of a hydrogel pellet.

[0145] In one embodiment, the ocular delivery system of the present invention is an electrospun ocular insert. Preferably, the ocular insert is formed only of a matrix of a pre-activated thiomer of hyaluronic acid, one or more anti-glaucoma drugs, optionally a non-pre-activated thiomer, and excipients, but does not include any additional layers or other materials.

[0146] The ocular insert can be obtained by direct compression of a mixture containing one or more glaucoma drugs dispersed in a preactivated thiomer of hyaluronic acid, which can be in lyophilized form.

[0147] The ocular insert may be of any shape and size, provided that it is suitable for placement on the eye, and is preferably in the shape of a rod, strip, screw, donut, disk, oval or quarter moon. In one embodiment, the ocular insert has one convex side and one concave side. The ocular insert does not exhibit any angles on its surface and presents a smooth surface that is non-irritating to the eye or eyelid. Preferably, the cross section of the ocular insert is circular, square or rectangular. Preferably, the insert is sized and shaped to easily fit on the eye, or a part thereof. In one embodiment, the ocular insert has a thickness in the range of 0.1 mm to 5 mm, preferably 0.5 mm to 2 mm, more preferably 0.5 mm to 1.5 mm. In one embodiment, the ocular insert has a length in the range of 1 mm to 10 mm, preferably 2 mm to 5 mm. In one embodiment, the ocular insert has a width in the range of 1 mm to 10 mm, preferably 2 mm to 5 mm.

[0148] In another embodiment, the solid or semi-solid ocular delivery system of the present invention is an ocular film, i.e., a solid or semi-solid robust two-dimensional film designed to be placed in the conjunctival sac or on the conjunctival surface, the size and shape of which are specifically designed for ophthalmic use. In one embodiment, the ocular film is in a dry form. In another embodiment, the ocular film is in a hydrated form.

[0149] The ophthalmic film may be square, circular, ellipsoid, or any other suitable shape. Preferably, the ophthalmic film has a thickness ranging from 0.01 μm to 1000 μm, preferably from 0.5 μm to 500 μm. If the ophthalmic film is a circular film, it may have a diameter ranging from 2 mm to 20 mm, preferably from 5 mm to 10 mm. The ophthalmic film may also have a curvature for suitable placement on the surface of the eye.

[0150] The ophthalmic film can be obtained by solvent evaporation of a solution containing the preactivated thiomer of hyaluronic acid and one or more anti-glaucoma drugs. Alternatively, the ophthalmic film can also be obtained by printing techniques, such as inkjet printing.

[0151] In one embodiment, the mucoadhesive solid or semi-solid ocular delivery system of the present invention is in a unit dosage form.

[0152] The present invention further relates to a kit comprising the solid or semi-solid ocular delivery system of the present invention. The kit may include instructions for use in the treatment of glaucoma. The kit may also include an applicator, preferably a sterile applicator. The kit may also include an eyewash if the delivery system needs to be removed from the eye.

[0153] Glaucoma Treatment The present invention also relates to the use of the mucoadhesive solid or semi-solid ocular delivery system of the present invention in the treatment of glaucoma. In particular, the ocular delivery system of the present invention is useful for delivering one or more anti-glaucoma drugs at the ocular level of a subject. The target ocular tissue can be, but is not limited to, corneal tissue, conjunctiva, eyelid, trabecular meshwork, iris, ciliary body, uveal tract, choroid, retina or macula. The ocular delivery system of the present invention is useful for human and veterinary applications.

[0154] In one embodiment, the present invention provides a mucoadhesive solid or semi-solid ocular delivery system of the present invention for use in the treatment of glaucoma.

[0155] The present invention also relates to the use of the mucoadhesive solid or semi-solid ocular delivery system of the present invention for the manufacture of a medicament for the treatment of glaucoma.

[0156] The present invention further relates to a method for treating glaucoma in a subject comprising placing a mucoadhesive solid or semi-solid ocular delivery system according to the present invention in the conjunctival sac or on the conjunctival surface of a subject in need thereof. The mucoadhesive solid or semi-solid ocular delivery system of the present invention is preferably placed in the ocular sac of a subject in need thereof.

[0157] In one embodiment, the glaucoma is open-angle glaucoma.

[0158] In one embodiment, use of the ocular delivery system of the present invention can reduce intraocular pressure in the eye of a subject. [Brief description of the drawings]

[0159] [Figure 1] FIG. 1 is a graph showing the dose (%) of bimatoprost released from inserts of formulation F1 over time in an in vitro release assay, calculated as the concentration of drug released relative to 100% theoretical concentration of drug released. [Diagram 2]FIG. 2 is a graph showing the dose (%) of bimatoprost released from inserts of Formulation F2 over time in an in vitro release assay. [Diagram 3] FIG. 3 is a graph showing the dose (%) of bimatoprost and timolol released from inserts of Formulation F3 over time in an in vitro release assay. EXAMPLES

[0160] The present invention is further illustrated by the following examples.

[0161] Example 1: Preparation of Ocular Inserts Ocular inserts according to the present invention were prepared with different formulations (F1-F4). [Table 1]

[0162] Two different preactivated thiomers of HA were used, which differ in molecular weight and in the degree of functionalization of the HA backbone with disulfide side chains, but have the same side chains, i.e., 2-(2-aminoethyl)disulfanayl)nicotinic acid (2-AMENA, corresponding to 2-MNA / cysteamine disulfide). These preactivated thiomers of HA were obtained by adapting the method described in US Patent Publication No. 2012 / 0225024, using hyaluronic acid as the polymer backbone, cysteamine as the ligand containing a free thiol group, and 2-mercaptonicotinic acid (2-MNA) as the preactivating group.

[0163] The non-preactivated thiomer of HA had cysteamine side chains, a molecular weight of 0.8 MDa and a degree of functionalization of 200 μmol / g. The non-preactivated thiomer of HA was obtained by adapting the method described in US Patent Publication No. 2012 / 0225024 using hyaluronic acid as the polymer backbone and cysteamine as the ligand containing a free thiol group.

[0164] The inserts were prepared by mixing all the components in powder form. For formulations F1 and F4, the powder mixture was first granulated by compression, followed by grinding and then compression. The inserts with formulations F2 and F3 were obtained by direct compression. 10 mg inserts were prepared (length 4.3 mm, width 2.3 mm, thickness 1.1 mm).

[0165] Example 2: In vitro mucoadhesion assay Objective: This in vitro assay aimed to determine the mucoadhesive properties of the inserts of the present invention by the rotating cylinder method, a visual test that evaluates the ability of the insert to remain on the mucosa while being subjected to shear.

[0166] Method: The inserts of Example 1 were placed on fresh animal mucosa. The mucosal surface was placed on a mesh disk (diameter 5 cm). The container of the dissolution test apparatus (Apparatus USP2-Method USP5-Paddle-over-disk apparatus) was filled with simulated tear fluid (Sodium bicarbonate, 0.2% w / w; Calcium chloride dihydrate, 0.008% w / w; Sodium chloride, 0.67% w / w; Ultrapure water, qsp; pH adjusted to 7.4 with HCl 5M) and the cylinder was rotated at a rotation speed of 50 rev / min at a temperature of 32° C. Detachment or disintegration of the insert was determined visually.

[0167] Results: The retention time of the inserts on the mucosa is reported in the table below. [Table 2]

[0168] Conclusion: The inserts according to the invention make it possible to achieve mucoadhesion for at least 2 days, and even for formulation F3 for 6 days.

[0169] Example 3: In vitro swelling assay Objective: This in vitro assay aims to determine the swelling behavior of the inserts of the present invention by measuring their ability to take up water.

[0170] Methods: Water uptake was determined gravimetrically: (1) the inserts of Example 1 were weighed (W0); (2) they were then immersed in simulated tear fluid (see Example 2) in a closed container to prevent evaporation during the assay and incubated at 32°C, the surface temperature of the eye; (3) at several time points the systems were removed and excess water was removed by gently wicking with tissue paper and reweighed (W t The water absorption (i.e., swelling ratio, wt%) was calculated as [(W t It is calculated as [-W0) / W0] × 100.

[0171] Results: The swelling ratios of the inserts are reported in the table below. [Table 3]

[0172] Conclusion: The swelling behavior of the inserts of the present invention can be adjusted by varying their composition.

[0173] Example 4: In vivo residence time evaluation Objective: This in vivo evaluation aimed to determine the residence time of the insert of the present invention by measuring the duration of the insert's presence in the lower conjunctival sac of rabbits as a result of its mucoadhesive properties, hydration and swelling behavior and formulation properties.

[0174] method:

[0175] Ocular inserts F5-F7, whose compositions are detailed below, were prepared as reported in Example 1. The preactivated thiomer of HA used in F5-F7 has the same side chain, 2-AMENA, as in Example 1, but has a different molecular weight (0.6 MDa) and a different degree of functionalization (110 μmol / g). The non-preactivated thiomer of HA is the same as in Example 1.

[0176] The swelling ratio was measured in vitro as in Example 3.

[0177] The retention period was measured as follows: the insert was measured in one direction in the lower conjunctival sac of New Zealand White rabbit eyes (n=3) by pulling the lower eyelid, and then the insert was placed with tweezers. The eyelid was returned to its normal position. The presence of the insert in the lower conjunctival sac was monitored twice a day (morning and afternoon) until the presence of the insert was no longer observed. The retention period of the insert in the lower conjunctival sac was then recorded.

[0178] result: [Table 4]

[0179] Conclusion: The residence time of the insert of the present invention on the ocular surface can be adjusted by varying the composition.

[0180] Example 5: Drug release profile Objective: The assay is intended to determine the drug release profile over time.

[0181] Method: The inserts from Example 1 were placed in a glass flask filled with 200 mL of purified water. The flask was placed in a shaking water bath at 32° C. Samples (10 mL) were taken at predetermined time points and 10 mL of purified water was added to maintain a total volume of 200 mL. In each sample, the concentration of released antiglaucoma drug was measured by HPLC-UV. Results are expressed as dose percent, calculated as the concentration of released drug relative to the theoretical concentration of 100% of released drug.

[0182] Results: The amount of antiglaucoma drug released from the inserts tested over time is reported in Figures 1, 2 and 3 for inserts of formulations F1, F2 and F3, respectively.

[0183] Conclusion: the inserts of the invention make it possible to achieve a controlled release of the antiglaucoma drug over time for at least 2 days. Formulation F3 even makes it possible to achieve a release over 6 days.

Claims

1. 1. A mucoadhesive solid or semi-solid ocular delivery system comprising: one or more anti-glaucoma drugs; and At least one pre-activated thiomer of hyaluronic acid selected from polymeric compounds having a hyaluronic acid backbone with covalently bound side chains comprising groups selected from 2-nicotinic acid-disulfide groups, 6-nicotinic acid-disulfide groups, 2-nicotinamide-disulfide groups, 2-isonicotinamide-disulfide groups, 6-nicotinamide-disulfide groups, 6-isonicotinamide-disulfide groups, and 6-pyridoxine-disulfide groups, wherein the pre-activated thiomer of hyaluronic acid has a molecular weight in the range of 100 kDa to 1200 kDa.

1. An ocular delivery system comprising:

2. The ocular delivery system of claim 1 which is an ocular insert or an ocular film.

3. The side chain of the preactivated thiomer of hyaluronic acid is S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-cysteine disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-homocysteine disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-cysteamine disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-N-acetylcysteine disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-thioglycolic acid disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-3-thiopropionic acid disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-4-thiobutanoic acid disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-mercaptobenzoic acid disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)- or S-(6-mercaptopyridoxine)-mercaptonicotinic acid disulfide, S-(2- or 6-mercaptonicotinic acid)-, S-(2- or 6-mercapto(iso)nicotinamide)-, or S-(6-mercaptopyridoxine)-glutathione disulfide, and S-(2- or 6-mercaptonicotinic acid), S-(2- or 6-mercapto(iso)nicotinamide), or S-(6-mercaptopyridoxine)-mercaptoaniline disulfide is selected from The side chains are independently attached to the hyaluronic acid backbone via amide or ester bonds. The ocular delivery system of claim 1 .

4. 2. The ocular delivery system of claim 1, wherein the pre-activated thiomer of hyaluronic acid comprises 10 μmol to 1350 μmol of mercaptonicotinic acid, mercaptonicotinamide, mercaptoisonicotinamide, or mercaptopyridoxine moieties per gram of polymer, preferably 100 μmol to 1350 μmol per gram of polymer.

5. 10. The ocular delivery system of claim 1, further comprising a non-preactivated thiomer, preferably a non-preactivated thiomer of hyaluronic acid.

6. the non-preactivated thiomer is selected from polymeric compounds having a hyaluronic acid backbone with covalently bound thiolated side chains selected from cysteine, homocysteine, N-acetylcysteine, cysteine ethyl ester, cysteamine, mercaptoaniline, adipic acid dihydrazide thiolated by reaction with iminothiolane, 5,5'-dithiobis(2-nitrobenzoic acid), dithiobis(propanoic acid dihydrazide), dithiobis(butyric acid dihydrazide), 3-(2-pyridyldithio)propionylhydrazide, dithiothreitol, ethylene sulfide, thioglycolic acid, 3-thiopropionic acid, 4-thiobutanoic acid, mercaptobenzoic acid, mercaptonicotinic acid, glutathione, and gamma-thiobutyrolactone; The side chains are independently attached to the hyaluronic acid backbone via amide, ether, or ester bonds. The ocular delivery system of claim 5 .

7. 10. The ocular delivery system of claim 1, wherein the pre-activated thiomer of hyaluronic acid and / or the non-pre-activated thiomer, if present, is cross-linked.

8. 2. The ocular delivery system of claim 1, wherein the anti-glaucoma drug is an intraocular pressure (IOP) lowering agent selected from a prostaglandin analog, a cholinergic agent, a beta-blocker, an alpha-adrenergic agent, a carbonic anhydrase inhibitor, a Rho kinase inhibitor, an NO donor, and combinations thereof.

9. 2. The ocular delivery system of claim 1, wherein the antiglaucoma drug is selected from latanoprost, bimatoprost, travoprost, tafluprost, latanoprost bunod, pilocarpine, echothiophate, carbachol, timolol, nadolol, carteolol, levobunolol, metipranolol, betaxolol, brimonidine, apraclonidine, dorzolamide, brinzolamide, acetazolamide, methazolamide, and netarsudil.

10. 10. The ocular delivery system of claim 1, comprising two antiglaucoma drugs, one a prostaglandin analogue and the other a beta-blocker, preferably bimatoprost and timolol.

11. The ocular delivery system of claim 1 , further comprising one or more pharmaceutically acceptable excipients.

12. 12. The ocular delivery system of claim 11, wherein the excipient is selected from thickeners, gelling agents, plasticizers, solubilizers, stabilizers, penetration enhancers, diluents, binders, glidants, channeling agents, lubricants and modified release agents.

13. The excipient may be selected from the group consisting of high molecular weight cross-linked polyacrylic acid polymers, polyvinyl alcohol, polyvinylpyrrolidone (also called povidone), cellulose, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose (also called hypromellose), carboxymethylcellulose, polyethylene glycol, hyaluronic acid, glycerol, cyclodextrin, glutathione in its reduced form, sorbitol, trehalose, xylitol, mannitol, sugars and their derivatives, sucrose, lactose, polysaccharides and their derivatives, magnesium stearate, dibasic lipase, cellulose acetate, cellulose acetate esters ...

12. The ocular delivery system of claim 11, wherein the active ingredient is selected from calcium phosphate, colloidal silicon dioxide, sodium chloride, polyoxyethylene stearate, lauryl sulfate, hydrogenated coco monoglycerides, hydrogenated coco monoglyceride diglycerides and hydrogenated coco monoglyceride triglycerides, glyceryl behenate, stearic acid, glyceryl palmitostearate, glyceryl dibehenate, glyceryl distearate, ammonium methacrylate copolymer (Type A), polyvinyl acetate-povidone copolymer, and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

14. The delivery system of claim 1, wherein the delivery system comprises one or more anti-glaucoma drugs in an amount of 0.01% to 50% (w / w) of the total weight of the delivery system; 5% to 80% w / w of at least one pre-activated thiomer of hyaluronic acid; 0% to 89.99% w / w of a non-preactivated thiomer of hyaluronic acid; and 0% to 94.99% w / w of one or more pharmaceutically acceptable excipients 10. The ocular delivery system of claim 1, comprising:

15. 10. The ocular delivery system of claim 1 for use in treating glaucoma in a subject in need thereof.

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